Otarmeni: what was done before first-in-human, and what came after?

“Study DB-OTO-001 was conducted in 7 US and 4 ex-US sites.”

“The selection of the proposed clinical dose concentration of 3 x 1013 vg/mL is supported by the pharmacodynamic modeling (OTOF-10116) of ABR improvements in the Otof-Q828X hom mouse model as well as the safety profile established in the GLP toxicology studies.”

“Single-dose toxicology studies were conducted in Otof-Q828X hom mice and cynomolgus monkeys.”

“The 2-month Good Laboratory Practice (GLP) study in adult mice, and the 3-month GLP study in juvenile mice, at dose levels up to 1.3 x 1011 vg/ear showed no DB-OTO-related adverse findings, with a no observed adverse effect level (NOAEL) of 1.3 x 1011 vg/ear.”

“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the IC route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”

“Across these nonclinical studies, there was negligible biodistribution of DB-OTO vector to the gonads, no expression of hOTOF mRNA in the gonads, and no gross or microscopic findings in the gonads, suggesting a low reproductive and germline integration risk.”

“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the IC route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”

“No carcinogenicity studies have been conducted with DB-OTO.”

“No carcinogenicity studies have been conducted with DB-OTO. These were considered not warranted based on a review of the animal toxicology studies, data from biodistribution studies showing limited DB-OTO vector distribution beyond the local compartment of the inner ear, and a lack of clinical evidence of carcinogenesis attributable to recombinant AAV vectors.”

“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the IC route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”